Nanostructured in vitro TB latency model

纳米结构体外结核潜伏期模型

• 批准号: 7876788
• 负责人: GRAHAM S TIMMINS
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876788
• 关键词: Aerobic; Animal Model; Anti-Infective Agents; Area; BCG Live; Bacillus (bacterium); Bacteria; Bacterial Model; Cells; Characteristics; Chemistry; Communities; Complement; Complex; Data; Disease; Drug Delivery Systems; Drug resistance; Figs - dietary; Film; Genus Mycobacterium; Goals; Growth; Human; Hybrids; In Vitro; Infection; Knowledge; Life; Lipids; Mediating; Metabolism; Methods; Modeling; Mus; Mycobacterium tuberculosis; Nanostructures; Nanotechnology; Oxygen; Pharmaceutical Preparations; Phenotype; Physiological; Preclinical Drug Evaluation; Publications; Recovery; Research; Resistance; Science; Silicon Dioxide; Solutions; Source; Structure; Testing; Time; Tuberculosis; Tuberculosis Vaccines; Work; X ray spectroscopy; X-Ray Diffraction; drug development; frontier; high throughput screening; implantation; in vitro Model; in vivo; in vivo Model; multidisciplinary; mycobacterial; nanobiology; nanostructured; novel; prevent; public health relevance; tool

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis latently persist in 2 billion people, representing a major reservoir of tuberculosis (TB) due to reactivation, yet the state of latent bacilli remains a mystery. In order to eradicate TB, we need to understand latency and develop in vitro models for drug screening. In this interdisciplinary project we have merged microbiological tuberculosis research with nanotechnology and novel materials. Recent publications demonstrate a unique phenomenon of cell-directed assembly of hybrid lipid-inorganic nanostructures that drive a unique non-replicative persistence, and protect bacteria and drastically prolong viability. We show these same structures can be formed using mycobacteria, and that they display the highly extended viability characteristic of latency. We hypothesize that the persistence of latent TB, and its resistance to chemotherapeutic challenge, can be modeled by incorporation of bacilli into self-assembled lipid-inorganic nanostructures. This model combines the ability for in vitro study and growth condition modulation, with the potential for in vivo implantation and infection. We will generate a new in vitro model for high throughput screening for targets of, and drugs that can eliminate latent TB, to complement the existing complex in vivo models and al- low this field to move forward. Specific Aim 1 Define the conditions for optimal lipid-inorganic nanostructure-encasement of mycobacteria and its effects upon mycobacterial resistance to drugs. Specific Aim 2 Determine the changes in mycobacterial metabolism occurring upon encasement in lipid- inorganic nanostructures that result from non-replicative persistence, and drive in vitro survival and latency. Specific Aim 3 Demonstrate that lipid-inorganic nanostructure-encased mycobacteria represent valid models of latency by showing their infectivity in mice, even after extended periods of time after assembly. PUBLIC HEALTH RELEVANCE: Public Health Relevance We need to understand the way that tuberculosis is able to exist in a latent state because it is present in 2 billion people worldwide and reactivates into an active form in a significant percentage of cases. Clearing this 'reservoir' will be an essential component of an eventual eradication strategy. Although there are animal models of latency, there is no good model of in vitro latency, yet we need to have such an in vitro model so that we can understand how to attack it, and also to screen drugs with. We have developed a unique nanostructured model that mimics the extreme non-replicative persistence of latency, and want to test how effective it might be as a tool in the battle against TB.

描述（由申请人提供）：结核分枝杆菌在20亿人中持续存在，代表了重生性结核病（TB）的主要水库，但潜在细菌的状态仍然是一个谜。为了消除结核病，我们需要了解潜伏期并开发用于药物筛查的体外模型。在这个跨学科项目中，我们将微生物结核病研究与纳米技术和新型材料合并。最近的出版物表明，杂交脂质无机纳米结构的细胞指导组装具有独特的现象，可驱动独特的非复制性持久性，并保护细菌并大幅度延长活力。我们表明可以使用分枝杆菌形成这些相同的结构，并显示出高度扩展的潜伏期生存能力。我们假设潜在结核的持久性及其对化学治疗挑战的耐药性可以通过将芽孢杆菌掺入自组装的脂质无机纳米结构中来建模。该模型结合了体外研究和生长状况调节的能力，并具有体内植入和感染的潜力。我们将生成一个新的体外模型，用于针对可以消除潜在结核的靶标的高通量筛选，以补充现有的体内复合体模型，并低下该领域以向前移动。具体目标1定义了分枝杆菌对最佳脂质无机纳米结构的最佳条件及其对分枝杆菌对药物的耐药性的影响。具体目标2确定脂质无机纳米结构的包膜发生的分枝杆菌代谢的变化，这些变化是由于非复制性持久性而导致的，并驱动了体外生存和潜伏期。具体目标3表明，即使在组装后延长了一段时间后，脂质无机纳米结构构成的分枝杆菌也代表了潜伏期的有效模型。 公共卫生相关性：公共卫生相关性，我们需要了解结核病能够在潜在状态下存在的方式，因为它在全球20亿人中存在，并在很大一部分案件中重新激活形式。清除此“水库”将是最终根除策略的重要组成部分。尽管有潜伏期的动物模型，但没有良好的体外潜伏期模型，但是我们需要具有这样的体外模型，以便我们可以理解如何攻击它，也可以使用筛查药物。我们已经开发了一个独特的纳米结构模型，该模型模仿了潜伏期的极端非复制性持久性，并希望测试它作为与结核病战斗的工具的有效性。